Multidrug resistance is a significant problem in the pharmaceutical industry, and may be achieved by the activation of cellular membrane transporters. Drugs and certain proteins are transported across the membranes of Gram-negative bacteria, for example, by energy-activated pumps. The outer membrane component of these pumps is a channel that opens from a sealed resting state during the transport process. ABCB1 exporter proteins confer drug resistance by pumping the drug out of the cell before the drug can function or exert its intended effect (e.g., kill a cancer cell). Classical inhibitors of the ABC exporter proteins are bulky hydrophobic molecules that overload the capacity of the hydrolysis of two ATP molecules to expel the drug by disruption of the hydrophobic associations, but these inhibitors lack specificity and are associated with significant side effects, disrupting important functions of ABC function in tissues throughout the body.
Methods for designing drugs and other therapeutic agents that are able to frustrate the activity of cellular exporter proteins and prevent expulsion of the drug or other therapeutic agent from a cell are greatly needed.